Functional Medicine for Chronic Fatigue: When “Just Tired” Is Something More
Author: Rohan Smith | Functional Medicine Practitioner | Adelaide, SA
Quick Answer
Persistent fatigue that does not improve with rest may reflect underlying biological dysfunction rather than lifestyle stress alone. Conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-viral fatigue, including long COVID, are associated with post-exertional malaise, immune dysregulation, mitochondrial dysfunction, and neuroinflammation (1–4). A functional medicine approach to chronic fatigue focuses on identifying and addressing these contributors rather than masking symptoms.
When Fatigue Stops Being “Normal”
Feeling tired after poor sleep or a demanding week is common. Chronic fatigue is different. When exhaustion persists for months, worsens after minimal exertion, and interferes with daily function, it suggests a systemic issue rather than simple overwork.
Many people describe waking already exhausted, experiencing “crashes” after minor activity, or never feeling restored by sleep. These features are characteristic of ME/CFS, which is defined by prolonged fatigue, post-exertional malaise, unrefreshing sleep, and cognitive impairment (1,2). A broader overview of how this is approached clinically is outlined in our chronic fatigue functional medicine guide.
A similar pattern is now widely observed following SARS-CoV-2 infection. Long COVID frequently includes persistent fatigue, neurological symptoms, and exercise intolerance months after the acute illness, with significant biological overlap with ME/CFS (3–5).
ME/CFS and Long COVID: Shared Biological Patterns
These conditions are not vague or psychological. Research increasingly demonstrates measurable physiological changes affecting energy production, immune regulation, and nervous system signalling.
Post-Exertional Malaise
Post-exertional malaise refers to a delayed and disproportionate worsening of symptoms following physical, cognitive, or emotional effort. Recovery may take days or weeks, reflecting impaired energy metabolism and abnormal stress responses (1,6).
Mitochondrial Dysfunction
Mitochondria generate cellular energy through oxidative phosphorylation. In chronic fatigue states, evidence suggests impaired mitochondrial function, reduced ATP generation, and altered metabolic pathways that directly contribute to energy depletion (7–9). Functional assessment of these pathways may involve specialised tools such as mitochondrial function testing.
Immune Dysregulation and Chronic Inflammation
Many individuals with ME/CFS or long COVID show signs of persistent immune activation, altered cytokine signalling, and reduced immune tolerance following infection or environmental stressors (4,10,11). Ongoing immune activation can also influence mood and cognition, which is explored further in our mental health and neuroinflammation resource.
Neuroinflammation and Autonomic Dysfunction
Inflammatory processes affecting the central nervous system may disrupt cognition, sleep regulation, and autonomic balance. Dysautonomia, including impaired heart rate and blood pressure regulation, is commonly reported in both ME/CFS and long COVID (12–14).
Why Standard Medical Testing Often Misses the Problem
Conventional blood tests are designed to detect overt disease rather than subtle system-level dysfunction. As a result, many individuals with chronic fatigue are told their results are “normal” despite persistent symptoms.
Standard panels rarely capture mitochondrial efficiency, inflammatory signalling patterns, hormonal rhythm disruption, or evolving immune changes over time (6,15).
Functional Medicine Testing: Looking at Patterns, Not Isolated Numbers
A functional medicine approach does not rely on a single abnormal marker. Instead, it evaluates trends, relationships, and physiological balance across interconnected systems.
Depending on clinical history, assessment may include:
- Expanded inflammatory markers and protein ratios
- Micronutrient status relevant to energy metabolism (e.g. B vitamins, magnesium, zinc)
- White blood cell differentials assessed longitudinally
- Diurnal cortisol and hormone rhythm evaluation, often using tools such as DUTCH adrenal testing
- Metabolic by-products associated with mitochondrial function
These findings help explain why symptoms persist and guide individualised care planning rather than symptom suppression.
Supporting Recovery: A Systems-Based Framework
Recovery from chronic fatigue is rarely achieved through a single intervention. Effective care addresses multiple physiological systems while respecting individual tolerance and recovery capacity.
Energy Metabolism Support
Nutrients involved in mitochondrial enzyme activity and cellular energy transfer may be considered when deficiencies or increased metabolic demand are identified (7,8).
Immune and Inflammatory Regulation
Reducing inappropriate immune activation and oxidative stress is often central to symptom improvement, particularly in post-viral fatigue states (4,10).
Restoring Hormonal and Circadian Rhythms
Disrupted cortisol rhythms and autonomic imbalance can perpetuate fatigue and sleep disturbance. Gradual rhythm restoration, rather than forced stimulation, is a core principle of care (12,15).
These strategies are not universal protocols and require individual assessment, pacing, and ongoing adjustment.
Frequently Asked Questions
How is chronic fatigue different from being “burnt out” or overwo
Burnout typically improves with rest, time off, and stress reduction. Chronic fatigue states such as ME/CFS or post-viral fatigue persist despite rest and are often characterised by post-exertional malaise, unrefreshing sleep, and cognitive impairment. These features suggest underlying biological dysfunction rather than simple lifestyle exhaustion.
Can exercise help with chronic fatigue?
Exercise tolerance varies significantly. In individuals with post-exertional malaise, pushing through fatigue can worsen symptoms and delay recovery. A functional approach prioritises pacing, energy management, and stabilisation of physiological systems before considering any graded physical activity.
Is functional medicine claiming to cure chronic fatigue?
No. Functional medicine does not promise cures. Its role is to identify contributing biological factors—such as immune dysregulation, mitochondrial stress, or hormonal rhythm disruption—and support these systems in a personalised way. Outcomes vary, and care is focused on improving function and quality of life rather than guaranteeing recovery.
Key Takeaway
Chronic fatigue and long COVID are not signs of weakness or poor motivation. They reflect underlying biological stress that standard testing often overlooks. Functional medicine chronic fatigue care aims to identify these drivers and support recovery through personalised, systems-based evaluation.
If persistent fatigue continues to limit daily life despite rest and reassurance, a deeper investigation may be warranted.
References
- Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. National Academies Press; 2015.
- Jason LA, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: symptoms and biomarkers. Front Pediatr. 2018.
- Davis HE, et al. Characterizing long COVID in an international cohort. EClinicalMedicine. 2021.
- Komaroff AL, Bateman L. Will COVID-19 lead to ME/CFS? Front Med. 2021.
- Nath A. Long-Haul COVID. Neurology. 2020.
- VanNess JM, et al. Postexertional malaise in CFS. J Chronic Fatigue Syndr. 2007.
- Missailidis D, et al. Mitochondrial dysfunction in ME/CFS. Int J Mol Sci. 2020.
- Tomas C, et al. Cellular bioenergetics in chronic fatigue syndrome. PLoS One. 2017.
- Myhill S, et al. Mitochondrial dysfunction and CFS. Int J Clin Exp Med. 2009.
- Montoya JG, et al. Cytokine signature in ME/CFS. Proc Natl Acad Sci USA. 2017.
- Rasa S, et al. Chronic viral infections in ME/CFS. J Transl Med. 2018.
- Raj SR, et al. Dysautonomia in ME/CFS. Auton Neurosci. 2018.
- Newton JL, et al. Autonomic dysfunction in CFS. QJM. 2007.
- Perrin R, et al. Brainstem dysfunction in chronic fatigue. Clin Neurophysiol Pract. 2018.
- Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr Rev. 2003.